Abstract
Combined inhibition of SHH and PI3K signaling synergistically blocks PTEN-deficient GBM growth.
Major finding: Combined inhibition of SHH and PI3K signaling synergistically blocks PTEN-deficient GBM growth.
Mechanism: Inhibition of SHH and PI3K suppresses S6K1, induces apoptosis, and promotes mitotic catastrophe.
Impact: Further clinical investigation of this combinatorial therapy in patients with GBM is warranted.
The tumor suppressor PTEN is frequently lost or inactivated in glioblastoma multiforme (GBM), resulting in aberrant activation of phosphoinositide 3-kinase (PI3K) signaling. However, targeted inhibition of PI3K alone has shown limited efficacy in PTEN-deficient GBM, suggesting that combined inhibition of other key pathways is necessary. Gruber Filbin and colleagues found that the sonic hedgehog (SHH) pathway was selectively activated in PTEN-deficient GBM tumors and in response to acute knockdown of PTEN in human GBM cells, suggesting inhibition of SHH and PI3K as a potential therapeutic strategy. In contrast to single-agent treatment, combined treatment with the PI3K inhibitor NVP-BKM120 and an inhibitor of the SHH receptor Smoothened, NVP-LDE225, synergistically reduced the viability of human PTEN-deficient GBM cells but not those expressing PTEN. Furthermore, simultaneous blockade of SHH and PI3K signaling diminished the intracranial growth of human GBM xenograft tumors and enhanced the survival of tumor-bearing mice. The antitumor effect of this inhibitor combination was mediated by reduced tumor-cell proliferation and cell size, increased apoptosis, and mitotic spindle defects that induced mitotic catastrophe. Moreover, in addition to targeted suppression of PI3K/AKT and SHH activity, treatment with NVP-BKM120 and NVP-LDE225 potentiated the inhibition of ribosomal protein S6 kinase 1 (S6K1) phosphorylation downstream of mTOR, suggesting that PI3K and SHH signaling intersect to coordinately activate S6K1. Consistent with the idea that suppression of S6K1 is critical for inhibition of tumor growth, administration of a small-molecule S6K1 inhibitor impaired GBM cell viability. These results support ongoing clinical studies on the safety and efficacy of this drug combination for patients with PTEN-deficient GBM.
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